Examining Dose-Related Effects of Oxytocin on Social Cognition Across Populations

Social cognitive impairments, particularly deficits and distortions in recognition and
interpretation of social cues and representations of thoughts, intentions, and feelings of
others—termed mentalization—are a key contributor to the pathology and morbidity of a number
of psychiatric disorders, including the schizophrenia spectrum, the autism spectrum and
personality disorders. Individuals with schizophrenia spectrum disorders have deficits in
social cognition (hypomentalization), while individuals with borderline personality disorder
seem to have exaggerated and distorted social cognition (hypermentalization). However, the
specificity and mechanisms of these impairments remain unclear. Therefore, a better
understanding of the modulation of social cognition is a priority for developing
interventions both pharmacologic and psychosocial. We propose here to examine the effects of
oxytocin, known to be a key regulator of social cognition through modulating frontolimbic
neural circuitry, on social cognition in schizotypal and borderline patients. In doing so, we
aim to characterize a model of optimum social cognitive activity to direct the development of
treatments, including dosing and target population-specific effects.

To this end, we propose to perform a 2-year study in which 105 patients, (45 with
schizophrenia spectrum disorders, 30 with borderline personality disorder, and 30 with autism
spectrum disorders) will perform 3 rounds of social cognition testing after three acute
single-dose treatment conditions (intranasal oxytocin dose of 24IU or 40IU or placebo)
separated by a washout period, in a repeated-measures, within-subjects, randomized,
placebo-controlled, double-blind, counterbalanced cross-over proof-of concept design. 30
healthy controls will not receive oxytocin/placebo and will perform 3 rounds of social
cognition tests separated by approximately 4 weeks, serving as a benchmark for normal
performance and a control for practice effects. Social cognitive testing will be performed 45
minutes after drug/placebo administration in an identical protocol each time. The social
cognitive test serving as primary outcome measure will be the Movie for the Assessment of
Social Cognition (MASC). We will also include other tests of social cognition and symptom
measures, to evaluate scope of effects. We will compare outcome measures at baseline (placebo
day) in schizotypal and borderline patients and healthy controls, and in schizotypal and
borderline patients across drug doses and placebo administration.

Furthermore, 60 subjects (15 HC, 15 with schizophrenia spectrum disorders, 15 BPD, and 15
with autism spectrum disorders, either new subjects or already enrolled subjects) will be
expected to complete an add-on MRI component of the study, after signing an additional
consent form. For the MRI portion of the study, these subjects will perform 2 more rounds of
social cognition testing after receiving double-blind intranasal oxytocin (40 IU) or placebo
in randomized order, in a cross-over, within-subjects design, separated by approximately a
1-week washout. The subjects will receive the study medication directly prior to beginning an
fMRI scan that will last approximately two hours. Oxytocin levels will be measured before
oxytocin administration and every 10-15 minutes until about 2 hours and 30 minutes
post-administration. The remainder of the protocol will remain the same.

Inclusion Criteria:

- 18 ≤ age ≤ 65

- Medically and neurologically healthy

- Willing and able to provide informed consent

- IQ≥80

Exclusion Criteria:

- Currently meets for a psychotic episode

- Clinically significant cardiovascular or neurological conditions, traumatic brain
injury, uncontrolled hypertension, clinically significant EKG abnormalities, or
serious general medical illness

- Clinical evidence of dehydration or significant hypotension; pregnant or lactating

- Currently meets DSM-IV-TR criteria for MDD

- Current substance abuse (last 6 months) or past dependence on stimulants, opioids or
other potentially neurotoxic drugs

- Currently taking psychotropic or other systemic medications

- Non-English speaking